Curcumin (CUR) is characterized as a yellow and hydrophobic herbal component that is originated from the turmeric plant (
Curcuma longa L. Zingiberaceae)
[29]. Growing evidence has shown some positive effects of
CUR in medicine, such as anti-tumor, anti-inflammatory, anti-oxidative, immunoregulatory, anti-fungus, and anti-bacterial features
[30][31], such as breast, ovarian, prostate, gastric, colorectal, pancreatic, and cervical cancers
[32][33][34][35]. Regarding anti-cancer mechanisms of
CUR, it has to be said that several signaling pathways are affected by that, for example, JAK (Janus Activated Kinase)/STAT (signal transducer and activator), PI3K (Phosphoinositide 3-kinases)/Akt, MAPK (mitogen-activated protein kinase), NF-ĸB, p53, Wnt/β-catenin, and apoptosis-related signaling (
Figure 3). Furthermore, CUR can suppress epithelial-mesenchymal transition (EMT), angiogenesis, proliferation, metastasis, and invasion of the tumor by modulating the expression of non-coding RNA (ncRNA) associated with the tumor
[36][37][38][39]. In the study of Shi et al., it was revealed that CUR can considerably suppress the growth and stimulate apoptosis in human OCa cell line Ho-8910. In their research, the use of 40 μM
CUR caused a reduction in pro-caspase-3, Bcl-X
L, and Bcl-2, whereas Bax and p53 levels were elevated in the treated cells with
CUR [35]. Triggering AMP-activated protein kinase (AMPK), which stimulates cell apoptosis and inhibits cell proliferation in several cancers, in a p38-dependent way is another mechanism of
CUR action in ovarian cancer cells CaOV3
[40]. In an animal investigation on OCa, it was manifested that
CUR can dramatically suppresses STAT3 and NF-ĸB signaling pathways
[41]. Liu et al. have pointed out that
CUR can stimulate human OCa cell autophagy through AKT/mTOR (mammalian target of rapamycin)/p70S6K pathway suppression
[42]. Despite these, the clinical application of
CUR has been limited owing to its instability and low water solubility, which in turn give rise to poor bioavailability of
CUR in cancerous cells. Attempts toward elevating the therapeutic effectiveness of Cur have been carried out through various techniques
[43]. An in vivo and in vitro investigation showed that nanocurcumin in combination with cisplatin, a common treatment for OCa, could lead to a remarked reduction of the weight and volume of ovarian tumors. In addition, this treatment decreased PI3K, JAK, TGF-β, Ki67 expression, and Akt phosphorylation
[44]. Hu et al. (2020) demonstrated that the use of Docetaxel curcumin/methoxy poly (ethylene glycol)-poly (L-lactic acid) (MPEG-PLA) copolymers nanomicelles cause the Suppression of tumor proliferation and angiogenesis (
Table 1). The study of Bondi et al. (2017) concluded that biocompatible Lipid nanoparticles as carriers improved curcumin efficacy in ovarian cancer treatment and caused the Reduction of cell colony survival, inhibition of tumor growth, and apoptosis induction (
Table 1). Dendrosomal nano-curcumin caused the reduction of cancer cell viability, a decrease of LncRNAs expression of H19 and HOTAIR, and an increase in the expression of MEG3 LncRNA and Bcl2 protein (
Table 1). The study of Sandhiutami et al. (2021) showed that co-use of curcumin nanoparticles and Cisplatin caused the Decrease of ovarian tumor weight and volume, reduction of PI3K, TGF-β, JAK, and Ki67 expression, Akt and STAT3 phosphorylation, and decrease of IL-6 level (
Table 1). In general, Curcumin is an efficient agent with anti-tumor, antioxidant, and anti-inflammatory activities. The main mechanisms of action by which curcumin exhibits its unique anticancer activity include inducing apoptosis and inhibiting proliferation and invasion of tumors by suppressing a variety of cellular signaling pathways.
Figure 3. Curcumin (CUR) and Quercetin (Que) can exert an anti-cancerous effect on ovarian cancer in many different pathways. CUR triggers AMP-activated protein kinase (AMPK) that leads to stimulation of cell apoptosis and inhibition of cell proliferation. Moreover, CUR can decrease pro-caspase-3, Bcl-XL, and Bcl-2 levels, whereas Bax and p53 levels rise in the treated cells with CUR. These changes lead to ovarian cancer treatment. Furthermore, CUR can exert a significant inhibitory effect on STAT3 and NF-ĸB signaling pathways. Quercetin (Que) can modify many pathways and play a role in ovarian cancer treatment. Que decreases the anti-apoptotic agents, like Bcl-2, Bcl-xL, while it elevates the expression of pro-apoptotic agents, such as Bad and Bid, leading to increased apoptosis and ovarian cancer treatment. In addition, the elevation of cytosolic Ca2+ levels due to Que consumption can take part in ovarian cancer treatment. Que triggers autophagy by endoplasmic reticulum (ER) stress by the p-STAT3/Bcl-2 axis as well. Bcl-XL, B-cell lymphoma-extra-large; BAX, BCL2-associated X protein; Bcl-2, B-cell lymphoma 2; Bad, BCL2 associated agonist of cell death; Bid, BH3-interacting domain death agonist; STAT, Signal transducer and activator of transcription; NF-ĸB, Nuclear factor-kappaB.
Table 1. Nano-based formulations of curcumin, quercetin, and resveratrol through various mechanisms affect ovarian cancer.
Type of Nano-Based Herbal Formulation |
Mechanism/Effect |
In Vivo/In Vitro |
References |
PLGA-phospholipid-PEG nanoparticles comprising curcumin |
Downregulation of P-glycoprotein |
In vitro |
[45] |
Niosome-encapsulated curcumin |
Arresting the cell cycle at the S phase and apoptosis induction |
In vitro |
[46] |
Docetaxel curcumin/methoxy poly (ethylene glycol)- poly (L-lactic acid) (MPEG-PLA) copolymers nanomicelles |
Suppression of tumor proliferation and angiogenesis |
In vivo/in vitro |
[47] |
Curcumin—loaded nanostructured lipid carrier |
Reduction of cell colony survival, inhibition of tumor growth, and apoptosis induction |
In vitro |
[48] |
Gemini curcumin |
Apoptosis induction |
In vitro |
[49] |
Curcumin and paclitaxel co-delivery by hyaluronic acid-modified drug-loaded polyethylenimine and stearic acid |
Downregulation of P-glycoprotein, and suppression of tumor cell migration |
In vivo/in vitro |
[50] |
Dendrosomal nano-curcumin |
Reduction of cancer cell viability, decease of LncRNAs expression of H19 and HOTAIR, and increase in the expression of MEG3 LncRNA and Bcl2 protein |
In vitro |
[51] |
Co-use of curcumin nanoparticles and Cisplatin |
Decrease of ovarian tumor weight and volume, reduction of PI3K, TGF-β, JAK, and Ki67 expression, Akt and STAT3 phosphorylation, and decrease of IL-6 level |
In vivo/in vitro |
[44] |
Encapsulated quercetin into monomethoxy poly (ethylene glycol)- poly (3-caprolactone) |
Apoptosis induction and the suppression of angiogenesis |
In vivo/in vitro |
[52] |
Encapsulated quercetin into methoxypoly(ethylene glycol) Poly(caprolactone) |
Apoptosis induction and cell growth suppression |
In vivo/in vitro |
[53] |
PEGylated liposomal quercetin |
Apoptosis induction, cell proliferation inhibition, and arresting the cell cycle at G0/G1 and G2/M phases |
In vivo/in vitro |
[54] |
Resveratrol—ZnO nanohybrid |
Mitochondrial membrane depolarization and ROS formation |
In vitro |
[55] |
RGD-conjugated Resveratrol human serum albumin nanoparticles |
Reduction of cell viability and tumor growth inhibition |
In vivo/in vitro |
[56] |
Resveratrol—bovine serum albumin nanoparticles |
Reduction of cancer cell growth, activation of cytochrome C, upregulation of caspase-3 and caspase-3 expression |
In vivo/in vitro |
[57] |